Gluconeogenesis Flashcards
(23 cards)
What is gluconeogenesis?
Glucose formation from non-carbohydrate precursors
Carbohydrates are important molecules in biological systems
Synthesis of carbohydrate containing biological molecules relies on a source of activated monosaccharides
In some situations these activated molecules are derived from noncarbohydrate precursors eg seedlings, bacteria, starving mammals
What is glucose? What is it needed for?
Primary fuel for the brain normally glucose
Only fuel for red blood cells is glucose
Daily requirement for glucose 160g (brain 120g)
Readily available glucose (sufficient for 1 day)
20g body fluids
190g glycogen
What is the major site of gluconeogenesis? What does it maintain?
Major site of gluconeogenesis is the liver (kidney during extreme starvation)
Helps maintain blood glucose levels so brain and muscle can extract it
Converts pyruvate into glucose
Not the reverse of glycolysis
Precursors first converted to pyruvate or enter pathway further along (at oxaloacetate or DHAP)
Why is the synthesis of glucose from non-carbohydrate precursors such an important pathway?
What are the major precursors of gluconeogenesis?
Lactate – skeletal muscle when glycolysis exceeds oxidative metaolism RBC
Amino acids – diet or during starvation (muscle breakdown) NOT LEUCINE OR LYSINE
Glycerol – hydrolysis of TAG yields glycerol and fatty acids
Glucose - (2ATP + 2NADH) - pyruvate
Pyruvate - (6 ATP + 2NADH) - glucose
Gluconeogenesis Vs Glycolysis
Equilibrium of glycolysis lies far in the direction of pyruvate production
Mostly due to the three irreversible reactions (hexokinase, PFK and pyruvate Kinase)
These reactions must be bypassed during gluconeogenesis
What are the irreversible steps in glycolysis?
Irreversible steps in glycolysis
Glucose + ATP -= glucose 6-phosphste + ADP
Fructose 6-phosphate + ATP = fructose 1,6-bisphosphate + ADP
Phosphoenolpyruvate + ADP = pyruvate + ATP
*these steps must be bypassed in gluconeogenesis
What is bypass one?
Bypass 1: pyruvate to PEP
Two step process
Step 1: Carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase
Anaplerotic reaction (fill up)
Step 2: decarboxylation and phosphorylation of oxaloacetate by Phosphoenolpyruvate Carboxykinase
GTP required (donates the phosphate group)
Enzyme located both cytosol and mitochondria
Mitochondrial Phosphoenolpyuvate Carboxylase used if lactate is glucogenic precursor (lactate to pyruvate yields NADH)
Cytosolic Phosphoenolpyruvate Carboxykinase used if pyruvate is glucogenic precurser (used if reducing equivalents low ie NADH needed)
What is mitochondrial phosphoenolpyruvate carboxykinase?
- mitochondrial phosphoenolpyruvate carboxykinase used if lactate is glucogenic precurser (lactate to pyruvate yields NADH)
- The NADH generated in the cytosol is used for the conversion of 1,3 bisPglycerate to glyceraldehyde 3 phosphate by the enzyme Glyceraldehyde 2-phosphate dehydrogenase further up the pathway
What is the oxaloacetate shuttle?
Cytosolic phosphoenolpyruvate is glucogenic precursor. (used if reducing equivalents low ie NADH needed)
Oxaloacetate cannot directly diffuse out
Converted to malate which leaves via specific transporter
Malate converted back to Oxaloacetate with concomitant production of NADH (required later)
Overall reaction of bypass 1?
Pyruvate + ATP + GTP + H20 = PEP + ADP + GDP + 2H+ + Pi
**Explain why there are two PEP carboxykinase enzymes (cytosolic and mitochondrial) in eukaryotes? **
What is bypass 2?
Bypass 2: Fructose 1,6-bisP to fructose 6-P
PEP is metabolised by the enzymes of glycolysis but in reverse until fructose 1,6-bisP is formed
The reactions are near equilibrium so when conditions favour gluconeogenesis they will be driven in the direction of Fructose 6-P is irreversible
The enzyme responsible is Fructose 1,6-bisphosphatase which is an allosteric enzyme that catalyses the hydrolysis of the C1 phosphate group
Fructose 1,6-bisphosphate + H2O = fructose 6-phosphate +Pi
What is bypass 3?
Bypass 3: Glucose 6-P to glucose
In most tissues conversion of fructose 6-P to glucose 6-P is the end of gluconeogenesis
However, tissues responsible for maintain blood glucose homeostasis (liver and kidney) need to convert glucose 6-P to glucose
Muscle cannot directly increase blood (glucose)
Takes place in ER
Explain why brain and skeletal muscle lack the glucose 6 phosphatase enzyme?
How are gluconeogenesis and glycolysis regulated?
Gluconeogenesis and glycolysis are reciprocally regulated
What is the cori cycle?
Lactate formed by active muscle in converted to glucose the liver
How is lactic acid produced during activity?
Vertebrates are mainly aerobic organisms (pyruvate is completely oxidised to CO2 and water)
During extreme muscular activity oxygen delivery to muscle is lower than oxygen requirements for oxidation of NADH
NADH is oxidised by transfer of electrons to pyruvate to form lactate
How is lactic acid produced during anaerobic activity?
Lactic acid dissociates to lactate and H+
The pH (-log(H+)) therefore decreases
Muscle pain and failure to contract
Activity decreases
Oxygen debt reduced in about 30 mins by conversion of lactic acid to glucose by gluconeogenesis in the liver
How does vertebrate size affect anaerobic metabolism?
Smaller vertebrates rarely rely on anaerobic metabolism eg migrating birds fly large distances without producing an oxygen debt
Larger vertebrates are often slow moving and rarely undertake intense muscular activity eg elephants and alligators
What is the cori cycle?
Lactate produce by active muscle and RBC
Lactate dead end product of metabolism
Well oxygenated cells convert lactate to pyruvate which enters TCA cycle eg cardiac muscle
Excess lactate enters liver and converted to glucose
Maintains blood glucose levels
What is the glyoxylate cycle?
Pathway by which plants and microorganisms can covert fatty acids (other compounds which yield acetyl coA) into glucose
Acetyl coA generated by b-oxidation is converted into glucose via glyoxylate cycle and gluconeogenesis
Decarboxylation reactions of TCA cycle bpassed so the carbon of acetyl coA is assimilated
Isocitrate cleaved to glyoxylate and succinate (metabolised by TCA enzymes to OA then glucose by gluconeogenesis)
Glycoxylate condenses with another acetyl coA to generate malate which is oxidised to generate OA for another round of the cycle
